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  • Review Article
  • Published:

The art and design of genetic screens: mouse

Nature Reviews Genetics volume 6, pages 557–567 (2005)Cite this article

Key Points

  • The post-genome challenge is to understand the relationship between our genetic code and physical form and to harness this knowledge to find treatments for disease.

  • The mouse is the pre-eminent experimental organism for modelling human disease and determining mammalian gene function.

  • Genetics — including the use of genetic screens — offers unsurpassed methods for unravelling complex biological problems.

  • Genetic screens fall into two broad categories: region-specific and genome-wide. Within these categories are a host of strategies that can be tailored to suit the aims of individual investigators, regardless of their biological focus.

  • Many of the tricks and techniques that have been so useful in lower organisms, such as balancer chromosome and modifier screens, are now being effectively pursued in the mouse.

  • Forward genetics in the mouse has been revolutionized since the sequencing of the mouse genome, as the traditional bottleneck — mutation identification — is now relatively simple and straightforward.

  • The technical aspects of mouse genetics will continue to become easier; the future is bright for researchers wishing to carry out genetic screens using mice.

Abstract

Humans are mammals, not bacteria or plants, yeast or nematodes, insects or fish. Mice are also mammals, but unlike gorilla and goat, fox and ferret, giraffe and jackal, they are suited perfectly to the laboratory environment and genetic experimentation. In this review, we will summarize the tools, tricks and techniques for executing forward genetic screens in the mouse and argue that this approach is now accessible to most biologists, rather than being the sole domain of large national facilities and specialized genetics laboratories.

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Figure 1: Classification of genetic screens.
Figure 2: Region-specific genetic screens.
Figure 3: Genome-wide genetic screens.
Figure 4: Mutation identification.

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References

  1. Keeler, C. E. The Laboratory Mouse, its Origins, Heredity and Culture (Harvard Univ. Press, Cambridge, 1931).

    Book  Google Scholar 

  2. Cuénot, L. La loi de Mendel et l'hérédite é de la pigmentation chez les Souris. Arch. Zool. Exp. Gen. 3, 27–30 (1902) (in French).

    Google Scholar 

  3. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002). This article presents the first analysis of the sequence of the mouse genome, the availability of which has revolutionized mouse genetics.

    Article  CAS  PubMed  Google Scholar 

  4. Hitotsumachi, S., Carpenter, D. A. & Russell, W. L. Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia. Proc. Natl Acad. Sci. USA 82, 6619–6621 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Russell, W. L. et al. Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc. Natl Acad. Sci. USA 76, 5818–5819 (1979). The authors describe the specific locus test, which represents an elegant example of an allelic non-complementation screen and also demonstrates the efficiency of ENU as a mutagen in the mouse.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Russell, W. L., Hunsicker, P. R., Carpenter, D. A., Cornett, C. V. & Guinn, G. M. Effect of dose fractionation on the ethylnitrosourea induction of specific-locus mutations in mouse spermatogonia. Proc. Natl Acad. Sci. USA 79, 3592–3593 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lyon, M. F. & Morris, T. Mutation rates at a new set of specific loci in the mouse. Genet. Res. 7, 12–17 (1966).

    Article  CAS  PubMed  Google Scholar 

  8. Beier, D. Sequence-based analysis of mutagenized mice. Mamm. Genome 11, 594–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Chen, Y. et al. Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells. Nature Genet. 24, 314–317 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Concepcion, D., Seburn, K. L., Wen, G., Frankel, W. N. & Hamilton, B. A. Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice. Genetics 168, 953–959 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Coghill, E. L. et al. A gene-driven approach to the identification of ENU mutants in the mouse. Nature Genet. 30, 255–256 (2002).

    Article  PubMed  Google Scholar 

  12. Kasarskis, A., Manova, K. & Anderson, K. V. A phenotype-based screen for embryonic lethal mutations in the mouse. Proc. Natl Acad. Sci. USA 95, 7485–7490 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Herron, B. J. et al. Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis. Nature Genet. 30, 185–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Goldowitz, D. et al. Large-scale mutagenesis of the mouse to understand the genetic bases of nervous system structure and function. Brain Res. Mol. Brain Res. 132, 105–115 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nolan, P. M. et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genet. 25, 440–443 (2000). References 15 and 26 present the results of the first large-scale genetic screens in the mouse.

    Article  CAS  PubMed  Google Scholar 

  16. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994). A classic paper that describes early screens and the heroic nature of identifying mutations before completion of the mouse genome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kapfhamer, D. et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nature Genet. 32, 290–295 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Hafezparast, M. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808–812 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Bannister, L. A., Reinholdt, L. G., Munroe, R. J. & Schimenti, J. C. Positional cloning and characterization of mouse mei8, a disrupted allelle of the meiotic cohesin Rec8. Genesis 40, 184–194 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Kile, B. T. et al. Functional genetic analysis of mouse chromosome 11. Nature 425, 81–86 (2003). This paper describes the use of a balancer chromosome to focus a screen on a defined genomic region.

    Article  CAS  PubMed  Google Scholar 

  21. Rathkolb, B. et al. The clinical-chemical screen in the Munich ENU Mouse Mutagenesis Project: screening for clinically relevant phenotypes. Mamm. Genome 11, 543–546 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Wu, J. Y. et al. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease. J. Clin. Invest. 113, 434–440 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Jun, J. E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003). References 23–25 are excellent examples of highly focused screens and the isolation of causative mutations in the post-genome era.

    Article  CAS  PubMed  Google Scholar 

  26. Hrabe de Angelis, M. H. et al. Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nature Genet. 25, 444–447 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Carpinelli, M. R. et al. Suppressor screen in Mpl−/− mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc. Natl Acad. Sci. USA 101, 6553–6558 (2004). This is the first example of a modifier screen in vertebrates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shima, N. et al. Phenotype-based identification of mouse chromosome instability mutants. Genetics 163, 1031–1040 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Blewitt, M. E. et al. An ENU screen for genes involved in variegation in the mouse. Proc. Natl Acad. Sci. USA 102, 7629–7634 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Percec, I. et al. An N-ethyl-N-nitrosourea mutagenesis screen for epigenetic mutations in the mouse. Genetics 164, 1481–1494 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Clark, A. T. et al. Implementing large-scale ENU mutagenesis screens in North America. Genetica 122, 51–64 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zarbalis, K. et al. A focused and efficient genetic screening strategy in the mouse: identification of mutations that disrupt cortical development. PLoS Biol. 2, e219 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Russell, W. L. X-ray-induced mutations in mice. Cold Spring Harb. Symp. Quant. Biol. 16, 327–336 (1951).

    Article  CAS  PubMed  Google Scholar 

  34. Marker, P. C., Seung, K., Bland, A. E., Russell, L. B. & Kingsley, D. M. Spectrum of Bmp5 mutations from germline mutagenesis experiments in mice. Genetics 145, 435–443 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cordes, S. P. & Barsh, G. S. The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell 79, 1025–1034 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Rinchik, E. M., Carpenter, D. A. & Selby, P. B. A strategy for fine-structure functional analysis of a 6- to 11-centimorgan region of mouse chromosome 7 by high-efficiency mutagenesis. Proc. Natl Acad. Sci. USA 87, 896–900 (1990). This is an excellent example of an extensive genetic analysis of a defined genomic interval using a deletion screen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rinchik, E. M. & Carpenter, D. A. N-ethyl-N-nitrosourea mutagenesis of a 6- to 11-cM subregion of the Fah–Hbb interval of mouse chromosome 7: Completed testing of 4557 gametes and deletion mapping and complementation analysis of 31 mutations. Genetics 152, 373–383 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Rinchik, E. M., Carpenter, D. A. & Johnson, D. K. Functional annotation of mammalian genomic DNA sequence by chemical mutagenesis: a fine-structure genetic mutation map of a 1- to 2-cM segment of mouse chromosome 7 corresponding to human chromosome 11p14–p15. Proc. Natl Acad. Sci. USA 99, 844–849 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kushi, A. et al. Generation of mutant mice with large chromosomal deletion by use of irradiated ES cells — analysis of large deletion around hprt locus of ES cell. Mamm. Genome 9, 269–273 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Thomas, J. W., LaMantia, C. & Magnuson, T. X-ray-induced mutations in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 95, 1114–1119 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. You, Y. et al. Chromosomal deletion complexes in mice by radiation of embryonic stem cells. Nature Genet. 15, 285–288 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Schimenti, J. C. et al. Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells. Genome Res. 10, 1043–1050 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Su, H., Wang, X. & Bradley, A. Nested chromosomal deletions induced with retroviral vectors in mice. Nature Genet. 24, 92–95 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. LePage, D. F., Church, D. M., Millie, E., Hassold, T. J. & Conlon, R. A. Rapid generation of nested chromosomal deletions on mouse chromosome 2. Proc. Natl Acad. Sci. USA 97, 10471–10476 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zheng, B. et al. Engineering a mouse balancer chromosome. Nature Genet. 22, 375–378 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Klysik, J., Dinh, C. & Bradley, A. Two new mouse chromosome 11 balancers. Genomics 83, 303–310 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Nishijima, I., Mills, A., Qi, Y., Mills, M. & Bradley, A. Two new balancer chromosomes on mouse chromosome 4 to facilitate functional annotation of human chromosome 1p. Genesis 36, 142–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Roderick, T. H. & Hawes, N. L. Nineteen paracentric chromosomal inversions in mice. Genetics 76, 109–117 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Chick, W. S., Mentzer, S. E., Carpenter, D. A., Rinchik, E. M. & You, Y. Modification of an existing chromosomal inversion to engineer a balancer for mouse chromosome 15. Genetics 167, 889–895 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pinto, L. H. & Takahashi, J. S. Functional Identification of Neural Genes (eds Chin, H. R. & Moldin, S. O.) 61–86 (CRC Press LLC, Boca Raton, 2001).

    Google Scholar 

  51. Shedlovsky, A., King, T. R. & Dove, W. F. Saturation germ line mutagenesis of the murine T region including a lethal allele at the quaking locus. Proc. Natl Acad. Sci. USA 85, 180–184 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Davis, A. P. & Justice, M. J. An Oak Ridge legacy: the specific locus test and its role in mouse mutagenesis. Genetics 148, 7–12 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Justice, M. J., Noveroske, J. K., Weber, J. S., Zheng, B. & Bradley, A. Mouse ENU mutagenesis. Hum. Mol. Genet. 8, 1955–1963 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Brown, S. D. & Peters, J. Combining mutagenesis and genomics in the mouse — closing the phenotype gap. Trends Genet. 12, 433–435 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Rastan, S. et al. Towards a mutant map of the mouse — new models of neurological, behavioural, deafness, bone, renal and blood disorders. Genetica 122, 47–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).

    Article  CAS  PubMed  Google Scholar 

  58. Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. King, D. P. et al. Positional cloning of the mouse circadian clock gene. Cell 89, 641–653 (1997). References 56–59 are classic papers that describe early screens and the heroic nature of identifying mutations before completion of the mouse genome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Anderson, K. V. Finding the genes that direct mammalian development: ENU mutagenesis in the mouse. Trends Genet. 16, 99–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Garcia-Garcia, M. J. et al. Analysis of mouse embryonic patterning and morphogenesis by forward genetics. Proc. Natl Acad. Sci. USA 102, 5913–5919 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hentges, K., Thompson, K. & Peterson, A. The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. Development 126, 1601–1609 (1999).

    CAS  PubMed  Google Scholar 

  63. Beutler, B., Crozat, K., Koziol, J. A. & Georgel, P. Genetic dissection of innate immunity to infection: the mouse cytomegalovirus model. Curr. Opin. Immunol. 17, 36–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Papathanasiou, P. et al. Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. Immunity 19, 131–144 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Nelms, K. A. & Goodnow, C. C. Genome-wide ENU mutagenesis to reveal immune regulators. Immunity 15, 409–418 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Silvers, W. K. The Coat Colours of Mice. A Model for Mammalian Gene Action and Interaction (Springer, New York, 1979).

    Google Scholar 

  68. Gunn, T. M. et al. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398, 152–156 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Perreault, N., Sackett, S. D., Katz, J. P., Furth, E. E. & Kaestner, K. H. Foxl1 is a mesenchymal modifier of Min in carcinogenesis of stomach and colon. Genes Dev 19, 311–315 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Silverman, K. A., Koratkar, R., Siracusa, L. D. & Buchberg, A. M. Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Res. 12, 88–97 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gould, K. A., Dietrich, W. F., Borenstein, N., Lander, E. S. & Dove, W. F. Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 144, 1769–1776 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dietrich, W. F. et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Casselton, L. & Zolan, M. The art and design of genetic screens: filamentous fungi. Nature Rev. Genet. 3, 683–697 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Forsburg, S. L. The art and design of genetic screens: yeast. Nature Rev. Genet. 2, 659–668 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Jorgensen, E. M. & Mango, S. E. The art and design of genetic screens: Caenorhabditis elegans. Nature Rev. Genet. 3, 356–369 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. St Johnston, D. The art and design of genetic screens: Drosophila melanogaster. Nature Rev. Genet. 3, 176–188 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Alexander, W. S., Roberts, A. W., Nicola, N. A., Li, R. & Metcalf, D. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 87, 2162–2170 (1996).

    CAS  PubMed  Google Scholar 

  78. Simon, M. A., Bowtell, D. D., Dodson, G. S., Laverty, T. R. & Rubin, G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67, 701–716 (1991).

    Article  CAS  PubMed  Google Scholar 

  79. Rubin, G. M. Signal transduction and the fate of the R7 photoreceptor in Drosophila. Trends Genet. 7, 372–377 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Simon, M. A. Signal transduction during the development of the Drosophila R7 photoreceptor. Dev. Biol. 166, 431–442 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Sandberg, M. L. et al. c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev. Cell 8, 153–166 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Silver, L. M. Mouse Genetics: Concepts and Applications (Oxford Univ. Press, New York, 1995).

    Google Scholar 

  83. Manly, K. F. & Olson, J. M. Overview of QTL mapping software and introduction to map manager QT. Mamm. Genome 10, 327–334 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Broman, K. W., Wu, H., Sen, S. & Churchill, G. A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Ihaka, R. & Gentleman, R. R: a language for data analysis and graphics. J. Comp. Graph. Stat. 5, 299–314 (1996).

    Google Scholar 

  86. Noveroske, J. K., Weber, J. S. & Justice, M. J. The mutagenic action of N-ethyl-N-nitrosourea in the mouse. Mamm. Genome 11, 478–483 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Huppi, K., Martin, S. E. & Caplen, N. J. Defining and assaying RNAi in mammalian cells. Mol. Cell 17, 1–10 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, Q. et al. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky–Pudlak syndrome types 5 and 6. Nature Genet. 33, 145–153 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Stanford, W. L., Cohn, J. B. & Cordes, S. P. Gene-trap mutagenesis: past, present and beyond. Nature Rev. Genet. 2, 756–768 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Ivics, Z., Hackett, P. B., Plasterk, R. H. & Izsvak, Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91, 501–510 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Luo, G., Ivics, Z., Izsvak, Z. & Bradley, A. Chromosomal transposition of a Tc1/mariner-like element in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 95, 10769–10773 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ivics, Z. & Izsvak, Z. A whole lotta jumpin' goin' on: new transposon tools for vertebrate functional genomics. Trends Genet. 21, 8–11 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Carlson, C. M. et al. Transposon mutagenesis of the mouse germline. Genetics 165, 243–256 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Quwailid, M. M. et al. A gene-driven ENU-based approach to generating an allelic series in any gene. Mamm. Genome 15, 585–591 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Rogers, D. C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Green, E. C. et al. EMPReSS: European Mouse Phenotyping Resource for Standardised Screens. Bioinformatics 12 April 2005 (10.1093/bioinformatics/bti441).

  97. Morgan, T. H. The Physical Basis of Heredity (eds Loeb, J., Morgan, T. H. & Osterhout, W. J. V.) (J. B. Lippincott Company The Washington Square Press, Philadelphia, 1919).

    Book  Google Scholar 

Download references

Acknowledgements

Research in the authors' laboratories is supported by a Program Grant from The National Health and Medical Research Council, Canberra, Australia, The Anti-Cancer Council of Victoria, Melbourne, Australia, The J.D. and L. Harris Trust, and The US National Institutes Of Health. B.T.K. is supported by a Queen Elizabeth II Fellowship from the Australian Research Council. We are grateful to N. Nicola, W. Alexander, K. Greig, M. Carpinelli and I. Majewski for critically reading this manuscript.

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Authors and Affiliations

  1. Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia

    Benjamin T. Kile & Douglas J. Hilton

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  1. Benjamin T. Kile
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Correspondence to Benjamin T. Kile or Douglas J. Hilton.

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Competing interests

Douglas J. Hilton is a founder of the biotechnology company MuriGen, and is a consultant to AMRAD Corporation. Benjamin T. Kile is a consultant to MuriGen.

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DATABASES

Entrez Gene

Apc

Atrn

Bmp5

Clock

Mafb

p

Trp53

Tyr

Wnt3

FURTHER INFORMATION

Australian Phenomics Facility

Children's Hospital Oakland Research Institute BAC/PAC Resources

Ensembl Mouse Genome Server

GNF Gene Expression Atlas

GSF — The ENU Screen

Ingenium Pharmaceuticals

International Gene Trap Consortium

Jackson Laboratory Mice Database

Jackson Laboratory Mouse Genome Informatics

Jackson Laboratory Mouse Heart, Lung, Blood, and Sleep Disorders Center

Lee Silver's 'Mouse Genetics' online

MIT Center for Genome Research Mouse STS Database

Mouse Gene Prediction Database

Mouse Mutagenesis for Developmental Defects

Mouse Phenome Database

MRC Mammalian Genetics Unit, Harwell

Mutant Mouse Regional Resource Centers

NCBI Mouse Genome Resources

Oak Ridge National Laboratory — Mammalian Genetics and Genomics

RIKEN (The Institute of Physical and Chemical Research)

Sanger Institute Mouse Genomics

UCSC Genome Bioinformatics

US Neuroscience Consortium

Glossary

MOUSE FANCY

A collection of enthusiasts interested in mice with unusual traits.

FORWARD GENETIC SCREEN

A genetic screen in which mutants are isolated on the basis of their phenotype. The mutation responsible is identified by positional cloning or by a candidate-gene approach.

ALLELIC SERIES

A series of alleles that are present at the same locus, which produce a gradient of phenotypes.

SHIRPA

A hierarchical protocol for the behavioural and pathological phenotyping of potential mouse models of neurological dysfunction.

EMPReSS

Individual phenotyping protocols that provide a platform for the systematic and standardized primary screening of mouse mutants.

EPIGENETIC

Any heritable influence (in the progeny of cells or of individuals) on chromosome or gene function that is not accompanied by a change in DNA sequence.

COMPOUND HETEROZYGOTE

A diploid genotype in which the two copies of a gene carry different mutations.

HAPLOINSUFFICIENT

A gene is haploinsufficient when loss of one functional copy in a diploid organism results in a phenotype.

HEMIZYGOUS

A diploid genotype that has only one copy of a particular gene, as in X-chromosome genes in a male, or when the homologous chromosome carries a deletion.

CRE–LOXP SYSTEM

A site-specific recombination system. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

CONDITIONAL SCREEN

A phenotypic screen in which animals, or cells taken from them, are challenged in order to test responses that are not ordinarily detectable in the steady state, for example, by exposure to a chemotherapeutic agent. Both hypo- and hyperresponsive mutants can be recovered.

HYPOMORPHIC

A partial loss-of-function allele, sometimes known as a 'weak' or 'leaky' allele.

THROMBOCYTOPENIA

Refers to a reduction in the number of circulating blood platelets.

ISOGENIC

Genetically identical; for example, two mice of the same inbred strain.

QUANTITATIVE TRAIT

A biological trait that shows continuous variation (such as weight) rather than falling into distinct categories (such as diseased or healthy).

PENETRANCE

The proportion of affected individuals among the carriers of a particular genotype. If all individuals with a disease genotype show the disease phenotype, then the disease is said to be 'completely penetrant'.

SIMPLE SEQUENCE LENGTH POLYMORPHISM

Simple dinucleotide and trinucleotide repeats that differ in length and, when amplified using PCR, give rise to the generation of fragments of different sizes.

GRAFT-VERSUS-HOST DISEASE

A destructive attack on host tissues by immune cells that are derived from a bone marrow transplant.

SMALL INTERFERING RNAS

Small antisense RNAs (20–25 nucleotides long), which are generated from specific dsRNAs, that trigger RNA interference. They serve as guides for the cleavage of homologous mRNA in the RNA-induced silencing complex.

INVERSE PCR

A method for cloning DNA that flanks a known sequence. Genomic DNA is digested and ligated into circles, and is then amplified by PCR. The primers used correspond to the known sequence, but point out from this sequence. In a circle that contains the known sequence, the unknown flanking sequence will be amplified.

GENE TRAPPING

A mutation strategy that uses insertion vectors to trap or isolate transcripts from flanking genes. The inserted sequence functions as a tag from which to clone the mutated gene.

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Kile, B., Hilton, D. The art and design of genetic screens: mouse. Nat Rev Genet 6, 557–567 (2005). https://doi.org/10.1038/nrg1636

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